Lupus Nephritis

Autoimmunity plays a major role in the pathogenesis of lupus nephritis. The immunologic mechanisms include production of autoantibodies directed against nuclear elements. Characteristics of the nephritogenic autoantibodies associated with lupus nephritis are as follows[1] :

• Antigen specificity directed against nucleosome or double-stranded DNA (dsDNA) - Some anti-dsDNA antibodies cross-react with the glomerular basement membrane

• Higher-affinity autoantibodies may form intravascular immune complexes, which are deposited in glomeruli

• Cationic autoantibodies have a higher affinity for the anionic glomerular basement membrane

• Autoantibodies of certain isotypes (immunoglobulin [Ig] G1 and IgG3) readily activate complement

These autoantibodies form pathogenic immune complexes intravascularly, which are deposited in glomeruli. Alternatively, autoantibodies may bind to antigens already located in the glomerular basement membrane, forming immune complexes in situ. Immune complexes promote an inflammatory response by activating complement and attracting inflammatory cells, including lymphocytes, macrophages, and neutrophils.[2, 3]

The histologic type of lupus nephritis that develops depends on numerous factors, including the antigen specificity and other properties of the autoantibodies and the type of inflammatory response that is determined by other host factors. In more severe forms of lupus nephritis, proliferation of endothelial, mesangial, and epithelial cells and the production of matrix proteins lead to fibrosis.[4]

Glomerular thrombosis is another mechanism that may play a role in pathogenesis of lupus nephritis, mainly in patients with antiphospholipid antibody syndrome, and is believed to be the result of antibodies directed against negatively charged phospholipid-protein complexes.[2]

Specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis. Azzouz and colleagues analyzed blood and fecal samples from 61 women with SLE and 17 healthy women. On rRNA amplification analysis, patients with SLE displayed a fivefold higher number of Gram-positive fecal bacteria, specifically Ruminococcus gnavus (RG). When the researchers stratified patients with SLE according to organ involvement, those with a history of kidney disease demonstrated an abundance of RG-specific amplicon sequence variant compared with those who had no renal impairment.[5]

Genetic factors

As with many autoimmune disorders, evidence suggests that genetic predisposition plays an important role in the development of both SLE and lupus nephritis. Multiple genes, many of which are not yet identified, mediate this genetic predisposition (see Table 1 below).[6, 7, 8, 9, 4, 10]

Table 1. Genes Associated With Systemic Lupus Erythematosus (Open Table in a new window)

SLE is more common in first-degree relatives of patients with SLE (familial prevalence, 10-12%). Concordance rates are higher in monozygotic twins (24-58%) than in dizygotic twins (2-5%), supporting an important role for genetics in the development of SLE. However, the concordance rate in monozygotic twins is not 100%, suggesting that environmental factors trigger development of clinical disease.

Human leukocyte antigen (HLA) class II genes include the following:

• HLA-DR2 and HLA-DR3 are associated with SLE
• HLA-DR4 is associated with a lower prevalence of SLE and appears to be protective

Complement genes include the following:

• C1Q, C1R, and C1S deficiencies are associated with SLE, lupus nephritis, and production of anti-dsDNA

• C2 and C4 deficiencies are associated with SLE or lupus-like syndrome

• C4A and C4B (possibly) gene deletions are associated with SLE

FcγR genes include the following:

• These mediate the binding of IgG and IgG-containing immune complexes to cells such as macrophages and other mononuclear phagocytes

• FcγRIIa binds to IgG2 and is encoded by 2 codominant alleles, H131 (or high affinity) and R131 (or low affinity); the low-affinity phenotype (homozygous for R131 allele; 131R/R) is associated with lupus nephritis in African Americans

• FcγRIIIa binds to IgG1 and is encoded by 2 codominant alleles, V158 (or high affinity) and F158 (or low affinity); the low-affinity phenotype (homozygous for F158 allele; 158F/F) is associated with SLE

Other relevant genes include the following:

• Cytokine genes - Certain polymorphisms of the IL10 gene (high producers) and possibly the IL1RN and TNFA genes (low producers) are associated with SLE

• Mannose-binding lectin genes - These gene polymorphisms are associated with an increased risk of SLE

• Apoptosis genes - Defects of several apoptosis genes are associated with lupuslike syndromes in mice and, rarely, SLE in humans, including CD95 (Fas) and CD178 (FasL)

Immunologic factors

The initial autoantibody response appears to be directed against the nucleosome, which arises from apoptotic cells.[4, 11, 12]

Patients with SLE have poor clearance mechanisms for cellular debris. Nuclear debris from apoptotic cells induces plasmacytoid dendritic cells to produce interferon-α, which is a potent inducer of the immune system and autoimmunity.[13, 14, 15]

Autoreactive B lymphocytes, which are normally inactive, become active in SLE because of a malfunction of normal homeostatic mechanisms, resulting in escape from tolerance. This leads to the production of autoantibodies. Other autoantibodies, including anti-dsDNA antibodies, develop through a process of epitope spreading. These autoantibodies develop over time, in an orderly fashion, months to years before the onset of clinical SLE.[16]

Frequency

In a multi-ethnic international cohort of patients enrolled within 15 months (mean, 6 months) after SLE diagnosis and assessed annually, lupus nephritis occurred in 700 of 1827 patients (38.3%). Lupus nephritis was frequently the initial presentation of SLE; it was identified at enrollment in 80.9% of cases. Patients with nephritis were younger, more frequently men and of African, Asian, and Hispanic race/ethnicity.[17]

In a study of a large Spanish registry, lupus nephritis was histologically confirmed in 1092 of 3575 patients with SLE (30.5%). The mean age at lupus nephritis diagnosis was 28.4 years. The risk for lupus nephritis development was significantly higher in men, in younger individuals, and in Hispanics. Patients receiving antimalarials had a significantly lower risk of developing lupus nephritis.[18]

Age-related demographics

Most patients with SLE develop lupus nephritis early in their disease course. SLE is more common among women in the third decade of life, and lupus nephritis typically occurs in patients aged 20-40 years.[19] Children with SLE are at a higher risk of renal disease than adults and tend to sustain more disease damage secondary to more aggressive disease and treatment-associated toxicity.[20, 21, 22]

Sex-related demographics

Because the overall prevalence of SLE is higher in females (ie, female-to-male ratio of 9:1), lupus nephritis is also more common in females; however, clinical renal disease has a worse prognosis and is more common in males with SLE.[19]

Race-related demographics

SLE is more common in African Americans and Asians than in white people, with the highest prevalence in Caribbean people. The prevalence of lupus nephritis is much higher in Asians than in Whites with SLE, but the 10-year renal outcome and renal survival rate appear to be better in Asians.[23] Particularly severe lupus nephritis may be more common in African Americans and Asians than in other ethnic groups.[19]

Over the past 4 decades, changes in the treatment of lupus nephritis and general medical care have greatly improved both renal involvement and overall survival. During the 1950s, the 5-year survival rate among patients with lupus nephritis was close to 0%. The subsequent addition of immunosuppressive agents such as intravenous (IV) pulse cyclophosphamide has led to documented 5- and 10-year survival rates as high as 85% and 73%, respectively.[24]

Mortality in patients with end-stage renal disease due to lupus nephritis has declined significantly in recent decades. The mortality rate per 100 patient-years declined from 11.1 in 1995-1999 to 6.7 in 2010-2014. Deaths due to cardiovascular disease declined by 44% and deaths due to infection declined 63%.[25]  

Morbidity associated with lupus nephritis is related to the renal disease itself, as well as to treatment-related complications and comorbidities, including cardiovascular disease and thrombotic events. Progressive renal failure leads to anemia, uremia, and electrolyte and acid-based abnormalities. Hypertension may lead to an increased risk of coronary artery disease and cerebrovascular accident.

Nephrotic syndrome may lead to edema, ascites, and hyperlipidemia, adding to the risk of coronary artery disease and the potential for thrombosis. The findings from one study indicate that patients with lupus nephritis, particularly early-onset lupus nephritis, are at increased risk for morbidity from ischemic heart disease.[26]

In a study of 56 children (< 18 years) with either global or segmental diffuse proliferative lupus nephritis, long-term renal outcomes were similar. Most patients reached adulthood but sustained significant renal damage. Complete remission rates were 50% and 60% in the global and segmental groups, respectively. Renal survival rates, defined as an estimated glomerular filtration rate of ≥60 mL/min/1.73 m2, were 93%, 78%, and 64 % at 1, 5, and 10 years, respectively, and corresponding patient survival rates were 98%, 96%, and 91%, respectively, with similar rates in the global and segmental groups.[27]

Therapy with corticosteroids, cyclophosphamide, and other immunosuppressive agents increases the risk of infection. Long-term corticosteroid therapy may lead to osteoporosis, avascular necrosis, diabetes mellitus, and hypertension, among other complications. Cyclophosphamide therapy may cause cytopenias, hemorrhagic cystitis, infertility, and an increased risk of malignancy.

Biomarkers of renal outcome in lupus nephritis include proteinuria and serum albumin. Studies have shown that a proteinuria cut-off of less than 0.7 or 0.8 g/day at 12 months predicts good long-term renal outcome. Domingues et al reported that serum albumin > 3.7 g/dL at 12 months predicts favorable renal outcome at 48 months.[28]

Patients with active lupus nephritis often have other symptoms of active systemic lupus erythematosus (SLE), including fatigue, fever, rash, arthritis, serositis, or central nervous system (CNS) disease. These are more common with focal and diffuse lupus nephritis.[29]

Some patients have asymptomatic lupus nephritis; however, during regular follow-up, laboratory abnormalities such as elevated serum creatinine levels, low albumin levels, or urinary protein or sediment suggests active lupus nephritis. This is more typical of mesangial or membranous lupus nephritis.

Symptoms related to active nephritis may include peripheral edema secondary to hypertension or hypoalbuminemia. Extreme peripheral edema is more common in persons with diffuse or membranous lupus nephritis, as these renal lesions are commonly associated with heavy proteinuria.[24]

Other symptoms directly related to hypertension that are commonly associated with diffuse lupus nephritis include headache, dizziness, visual disturbances, and signs of cardiac decompensation.

With focal and diffuse lupus nephritis, the physical examination may reveal evidence of generalized active SLE with the presence of a rash, oral or nasal ulcers, synovitis, or serositis. Signs of active nephritis are also common.

With active lupus nephritis, patients have hypertension, peripheral edema, and, occasionally, cardiac decompensation.

With membranous lupus nephritis, signs of an isolated nephrotic syndrome are common. These include peripheral edema, ascites, and pleural and pericardial effusions without hypertension.

Evaluating kidney function in patients with systemic lupus erythematosus (SLE) to detect any kidney involvement early is important because early detection and treatment can significantly improve renal outcome.[24]

Kidney biopsy should be considered in any patient with SLE who has clinical or laboratory evidence of active nephritis, especially upon the first episode of nephritis.[24, 30]

Lupus nephritis is staged according to the classification revised by the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) in 2013. This classification is based on light microscopy, immunofluorescence, and electron microscopy findings from kidney biopsy specimens.

Laboratory tests to evaluate kidney function in SLE patients include the following:

• Blood urea nitrogen (BUN) testing

• Serum creatinine assessment

• Urinalysis (to check for protein, red blood cells [RBCs], and cellular casts)

• A spot urine test for creatinine and protein concentration (normal creatinine excretion is 1000 mg/24 h/1.75 m2; normal protein excretion is 150-200 mg/24 h/1.75 m2; normal urinary protein-to-creatinine ratio is < 0.2)

• A 24-hour urine test for creatinine clearance and protein excretion

In an international study, Smith and colleagues reported that a panel of novel urinary biomarkers can accurately identify active lupus nephritis in children.[31] These authors concluded that the optimal biomarker panel would include the following:

• Alpha-1-acid glycoprotein (AGP)
• Ceruloplasmin
• Lipocalin-like prostaglandin D synthase (LPGDS)
• Transferrin (area under the curve [AUC] 0.920)

SLE disease activity can be evaluated by assessing antibodies to double-stranded DNA (dsDNA), complement (C3, C4, and CH50), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels.

The CRP level is generally not elevated in patients with SLE, even with active disease, unless the patient has significant arthritis or infection.[24] Generally, elevated ESR and anti-dsDNA and depressed C3 and C4 levels are associated with active nephritis, especially focal and diffuse lupus nephritis. Clinically relevant lupus nephritis is associated with a 30% decrease in creatinine clearance, proteinuria of greater than 1000 mg/d, and/or renal biopsy findings indicating active lupus nephritis.

Anti-nucleosome antibodies appear early in the course of the autoimmune response in SLE, they have high sensitivity and specificity for a diagnosis of SLE, and the titers correlate with disease activity.[32, 33, 34] Anti-C1q antibodies are associated with lupus nephritis; higher titers correlate with active renal disease.[35, 36]

Anti-C1q antibodies have a sensitivity of 44-100% and a specificity of 70-92% in active renal disease (SLE); in combination with low C3 and C4 levels, these may be the predictors of renal flares in patients with SLE.[37] Although anti-DNA antibodies were more sensitive than anti-C1q antibodies for active lupus nephritis (75% vs 53%, respectively), anti-C1q antibodies were more specific (84% vs 49%, respectively); the negative predictive value of negative anti-DNA and anti-C1q antibodies for active lupus nephritis was 91%.[38]

Kidney biopsy may be useful in patients with recurrent episodes of nephritis, depending on the clinical circumstances. By revealing the histologic pattern and stage of disease (activity and chronicity), kidney biopsy is useful in determining prognosis and treatment. Findings from a thorough clinical and laboratory evaluation can be used to predict the histologic type of lupus nephritis in approximately 70-80% of patients; however, this is not accurate enough, in view of the toxicity of some of the treatment protocols.

A good rule is to perform a kidney biopsy if the findings will potentially alter patient management. If a particular patient has other manifestations of SLE (eg, severe central nervous system [CNS] or hematologic involvement) and will be treated with cyclophosphamide, biopsy may not be necessary but should still be considered because it may help predict renal outcome.

Sampling error can occur during a kidney biopsy. Thus, the results of the biopsy should always be evaluated for consistency with the clinical and laboratory presentation of the patient.

The experience of pathologists in reading lupus nephritis biopsy specimens varies considerably. Studies have suggested that the most consistent readers are in larger medical centers with substantial populations of patients with SLE.[39]

The classification of lupus nephritis was revised by the International Society of Nephrology and the Renal Pathology Society (ISN/RPS) in 2003 and is based on light microscopy, immunofluorescence, and electron microscopy findings from kidney biopsy specimens. The ISN/RPS classification itself is based on earlier classifications by the World Health Organization (WHO) in 1974 and 1982 (see Table 2 below).[40] Further revision of the ISN/RPS classification, proposed in 2018, includes elimination of the class IV-S and IV-G subdivisions of class IV lupus nephritis and replacement of the active and chronic designations for class III/IV lesions by a proposal for activity and chronicity indices to be applied to all classes.[41]

Table 2. International Society of Nephrology/Renal Pathology Society 2003 Classification of Lupus Nephritis (Open Table in a new window)

In addition to the pathologic classification, activity and chronicity indices are scored pathologically and predict the renal prognosis—that is, the progression of renal disease (see Table 3 below). The activity index reflects the state of active inflammation observed at biopsy, which may be reversible with medical therapy. The chronicity index reflects the amount of fibrosis and scarring, which are unlikely to respond to therapy. Renal lesions with a high activity index are more likely to respond to aggressive therapy, whereas renal lesions with high chronicity are not.

These indices in the table below serve as a prognostic tool and a general guide to therapy. Signs of activity justify aggressive medical therapy because such therapy may arrest or reverse the pathologic changes. Signs of chronicity suggest irreversibility, and aggressive therapy is less likely to affect the outcome. The activity and chronicity indices are evaluated at a single point in time, and renal lesions may transform from one class to another either spontaneously or as a result of treatment.

Table 3. Active and Chronic Glomerular Lesions (Open Table in a new window)

See the images below.

Mesangial proliferative lupus nephritis with moderate mesangial hypercellularity. International Society of Nephrology/Renal Pathology Society 2003 class II (×200, hematoxylin-eosin).

Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×100, hematoxylin-eosin).

Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×200, immunofluorescence).

Diffuse lupus nephritis with hypertensive vascular changes. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).

Diffuse lupus nephritis with early crescent formation. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).

Diffuse lupus nephritis with extensive crescent formation (rapidly progressive glomerulonephritis). International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).

Membranous lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, hematoxylin-eosin).

Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, silver stain).

Advanced sclerosis lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class VI (×100, hematoxylin-eosin).

The principal goal of therapy in lupus nephritis is to normalize kidney function or, at least, to prevent the progressive loss of kidney function. Therapy differs depending on the pathologic lesion.[24, 42] It is important to treat extrarenal manifestations and other variables that may affect the kidneys. Patients should be on hydroxychloroquine if possible, as data suggest that this improves outcomes in patients who have lupus nephritis, in addition to reducing lupus-related flares and disease damage accrual.[43]

Corticosteroid therapy should be instituted if the patient has clinically significant renal disease. Use immunosuppressive agents, particularly cyclophosphamide, azathioprine, or mycophenolate mofetil, if the patient has aggressive proliferative renal lesions, as they improve the renal outcome. Immunosuppressives can also be used if the patient has an inadequate response or excessive sensitivity to corticosteroids.[42, 44, 45, 39]

Calcineurin inhibitors, especially tacrolimus, have demonstrated benefit in lupus nephritis. However, most studies have been limited to Asian patients, and further research is required on long-term benefits and disadvantages.[46, 47, 48, 39]  The calcineurin inhibitor voclosporin is the first oral therapy approved by the US Food and Drug Administration (FDA) for lupus nephritis in conjunction with immunosuppressive treatment.[49]

Leflunomide, a pyrimidine synthesis inhibitor that is approved by the FDA for use in rheumatoid arthritis, has shown efficacy in proliferative lupus nephritis in Chinese patients.[50, 51]  More recent evidence indicates that leflunomide may also have some efficacy in lupus nephritis in patients of other ethnic groups.

Treat hypertension aggressively. On the basis of beneficial effects in other nephropathies, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been routinely used to treat proteinuria in lupus nephritis.

Alter the diet according to the presence of hypertension, hyperlipidemia, and renal insufficiency. Restrict fat intake or use lipid-lowering therapy such as statins for hyperlipidemia secondary to nephrotic syndrome. Restrict protein intake if renal function is significantly impaired.

Administer calcium supplementation to prevent osteoporosis if the patient is on long-term corticosteroid therapy, and consider adding a bisphosphonate (depending on renal function).

Avoid drugs that affect renal function, including nonsteroidal anti-inflammatory drugs (NSAIDs), especially in patients with elevated creatinine levels. Nonacetylated salicylates can be used to safely treat inflammatory symptoms in patients with renal disease.

Patients with active lupus nephritis should avoid pregnancy, because it may worsen their renal disease and because certain medications used in the treatment may be teratogenic.[52] In women who desire pregnancy, the following approach is advised[53] :

• A preconception evaluation to establish and inform the patient about pregnancy risks
• Plan for pregnancy during inactive lupus nephritis
• Keep the lupus nephritis inactive with the lowest possible dosage of allowed drugs
• Treat known risk factors (hypertension, antiphospholipid and antibodies)
• Monitor closely during and after pregnancy to rapidly identify and treat SLE flares and obstetric complications

Patients with end-stage renal disease (ESRD), sclerosis, and a high chronicity index based on renal biopsy findings are unlikely to respond to aggressive therapy. In these cases, focus therapy on extrarenal manifestations of systemic lupus erythematosus (SLE) and on possible kidney transplantation.

Classes I and II

Minimal mesangial (class I) lupus nephritis requires no specific therapy.[24]

Mesangial proliferative (class II) lupus nephritis may require treatment if proteinuria is greater than 1000 mg/day. Consider prednisone in low-to-moderate doses (ie, 20-40 mg/day) for 1-3 months, with subsequent taper.

Classes III and IV

Patients with either focal (class III) or diffuse (class IV) lupus nephritis are at high risk of progressing to ESRD and thus require aggressive therapy.

Administer prednisone 1 mg/kg/day for at least 4 weeks, depending on clinical response. Then, taper it gradually to a daily maintenance dose of 5-10 mg/day for approximately 2 years. In acutely ill patients, intravenous (IV) methylprednisolone at a dosage of up to 1000 mg/day for 3 days may be used to initiate corticosteroid therapy.

In patients who do not respond to corticosteroids alone, who have unacceptable toxicity to corticosteroids, who have worsening renal function, who have severe proliferative lesions, or who have evidence of sclerosis on renal biopsy specimens, use immunosuppressive drugs in addition to corticosteroids.

Both cyclophosphamide and azathioprine are effective in proliferative lupus nephritis, although cyclophosphamide is apparently more effective in preventing progression to ESRD. Mycophenolate mofetil has been shown to be at least as effective as intravenous (IV) cyclophosphamide, with less toxicity, in patients with focal or diffuse lupus nephritis who have stable renal function.[54, 55] It may be used alone[54, 55] or sequentially after a 6-month course of IV cyclophosphamide.[56]

Administer IV cyclophosphamide monthly for 6 months and every 2-3 months thereafter, depending on clinical response. The usual duration of therapy is 2-2.5 years. Reduce the dose if the creatinine clearance is less than 30 mL/min. Adjust the dose depending on the hematologic response.[57, 58]  The gonadotropin-releasing hormone analog leuprolide acetate has been shown to protect against ovarian failure.[59]

Shorter courses and lower doses of IV cyclophosphamide are used currently, which reduces the overall toxicity of cyclophosphamide. Sequential therapy with monthly IV cyclophosphamide for 6 months followed by mycophenolate mofetil[56] or Euro-Lupus dosing, which is 500 mg of IV cyclophosphamide every 2 weeks for 3 months followed by azathioprine.[60]  Both of those regimens have been shown to be effective in proliferative lupus nephritis.

Appel et al studied 370 patients with lupus nephritis in a randomized open-label study and found no significant difference in clinical improvement was observed with mycophenolate mofetil compared with IV cyclophosphamide.[61] The study included induction and maintenance therapy, and both study groups received prednisone.

Azathioprine can also be used as a second-line agent, with dose adjustments depending on hematologic response.

Mycophenolate mofetil was found to be superior to azathioprine in maintaining control and preventing relapses of lupus nephritis in patients who have responded to induction therapy.[62]

In a 10-year follow-up of the MAINTAIN Nephritis Trial, which compared azathioprine and mycophenolate mofetil as maintenance therapy of proliferative lupus nephritis, Tamirou and colleagues found that the two treatments resulted in similar outcomes. Two deaths and one case of end-stage renal disease developed in the azathioprine group, versus three deaths and three cases of end-stage renal disease in the mycophenolate mofetil group.[63]

Class V

Patients with membranous lupus nephritis are generally treated with prednisone for 1-3 months, followed by tapering for 1-2 years if a response occurs. If no response occurs, the drug is discontinued. Immunosuppressive drugs are generally not used unless renal function worsens or a proliferative component is present on kidney biopsy specimens. Some clinical evidence indicates that azathioprine, cyclophosphamide, cyclosporine, and chlorambucil are effective in reducing proteinuria. Mycophenolate mofetil may also be effective. European guidelines recommend mycophenolate mofetil as first choice for class V disease, with calcineurin inhibitors (especially tacrolimus) as alternative options.[64]

In a study of membranous lupus nephritis, 38 patients were treated with corticosteroids and azathioprine; after 12 months of treatment, 67% of patients had a complete remission and 22% had a partial remission, with only 11% resistant to treatment.[65] Long-term follow-up of 12 years showed 19 episodes of renal flares. Retreatment with corticosteroids and azathioprine showed similar responses.

Belimumab (Benlysta) is an anti–B-lymphocyte stimulator [BLyS] monoclonal antibody).[66]  It is approved by the US Food and Drug Administration (FDA) to treat adults with active lupus nephritis who are receiving standard therapy.

Efficacy was based on a phase III, BLISS-LN trial that randomized patients (n=448) with lupus nephritis—including patients with focal (class III), diffuse (class IV), and membranous (class V) lupus nephritis—to receive either belimumab or placebo with standard therapy. The Primary Efficacy Renal Response (PERR) was significantly higher in the belimumab arm than the placebo arm at Week 52 (47% versus 35%, respectively) and Week 104 (43% versus 32%, respectively). Patients in the belimumab group also had improved outcomes, including complete renal response (CRR) over a 2-year period.[67]

Voclosporin (Lupkynis), a calcineurin inhibitor, is the first FDA-approved oral therapy used in combination with immunosuppressive therapy for lupus nephritis. Approval was based on data from 2 clinical trials, the phase III AURORA trial and the phase II AURA-LV trial. Both studies enrolled patients with lupus nephritis of Class III or IV (alone or in combination with Class V) or pure Class V.

The AURA-LV study randomized patients to placebo or an induction regimen that combined voclosporin with mycophenolate mofetil and low-dose oral corticosteroids. CRR at week 24 was achieved by 32.6% in the low-dose voclosporin group, 27.3% in the high-dose voclosporin group, and 19.3% in the placebo group. The CRR rate in the low-dose and high-dose voclosporin groups was higher compared with placebo at 48 weeks.[68]  

The phase III AURORA trial compared the efficacy and safety of voclosporin (23.7 mg twice daily) with placebo in combination with mycophenolate and low-dose oral corticosteroids. At 1 year, the renal response rate was higher in the voclosporin group than in the placebo group (40.8% vs 22.5%; odds ratio, 2.65; P < 0.001). In addition, the median time to the achievement of a urine protein-to-creatinine ratio below 0.5 mg/mg was significantly and clinically better with voclosporin than with placebo (169 vs 372 days; log rank P < 0.001).[69]

Rituximab

B-lymphocytes play a pivotal role in the pathogenesis of SLE, which makes rituximab, a B-lymphocyte–depleting therapy, an attractive therapeutic option in SLE and lupus nephritis.[70]  In meta-analyses, rituximab has proved effective, especially in lupus nephritis that is refractory to standard therapy.[71]  Most of the studies have been retrospective, but one prospective observational single-center cohort study demonstrated the efficacy of a steroid-sparing regimen of rituximab and mycophenolate mofetil for lupus nephritis. For the study, Condon et al treated 50 consecutive patients 2 doses of rituximab (1 g) and methylprednisolone (500 mg) on days 1 and 15, and mycophenolate mofetil for maintenance therapy. By 52 weeks, 52% of patients had achieved complete biochemical remission and 34% had achieved partial remission.[72]

However, despite wide clinical use, rituximab remains a controversial choice for lupus nephritis, due to the lack of robust supporting evidence and some negative results. For example, a randomized, double-blind, phase II/III trial of rituximab in moderately-to-severely active SLE (EXPLORER) failed to show differences compared with placebo, although a beneficial effect of rituximab was noted in the African-American and Hispanic subgroups.[73]   A randomized, double-blind, phase III trial of rituximab in active proliferative lupus nephritis (LUNAR) showed that rituximab therapy resulted in more responders and greater reductions in anti-DNA antibodies in increases in C3 and C4 levels, but it did not improve clinical outcomes after 1 year of treatment.[74]

Other anti-CD20 monoclonal antibodies

Other anti-CD20 monoclonal antibodies have been used experimentally for lupus nephritis; for example, in patients who respond to rituximab but develop intolerable adverse effects. Case series have described benefit with ofatumumab.[75, 76]  In a phase III trial of ocrelizumab for class III/IV lupus nephritis, overall renal response rates with ocrelizumab were numerically but not statistically significantly superior to those with placebo, and the trial was terminated early because of higher rates of serious infections in patients receiving ocrelizumab and background mycophenolate mofetil.[77]

Atacicept

Atacicept is a TACI-Ig fusion protein that inhibits BLyS and a proliferation-inducing ligand [APRIL]).[66] In early phase studies, atacicept was demonstrated to have biologic effects in patients with SLE, resulting in a dose-dependent reduction in B cells and immunoglobulin levels.[78]

Abetimus

Abetimus is a B-lymphocyte tolerogen that was found to be ineffective in preventing flares of lupus nephritis in a large controlled trial, although it did reduce levels of anti-DNA antibodies.[79]

Anticytokine therapies

Various anticytokine therapies have been proposed, including monoclonal antibodies directed against the following[66] :

• Interferon-α
• Interleukin (IL)-1
• IL-6
• IL-10
• Tumor necrosis factor alpha (TNF-α)

Patients with ESRD require dialysis and are good candidates for kidney transplantation (see Kidney Transplantation). Patients with ESRD secondary to SLE represent 1.5% of all patients on dialysis in the United States. The survival rate among patients on dialysis is fair (5-year survival rate, 60-70%) and is comparable with that among patients on dialysis who do not have SLE.

Hemodialysis is preferred to peritoneal dialysis; several studies have documented higher levels of antibodies to double-stranded DNS (dsDNA), more thrombocytopenia, and higher steroid requirements in patients with SLE and ESRD who are on peritoneal dialysis. Hemodialysis also has anti-inflammatory effects with decreased T-helper lymphocyte levels. SLE is generally quiescent in patients on hemodialysis, although flares, including rash, arthritis, serositis, fever, and leukopenia may occur, necessitating specific treatment.

Patients with SLE account for 3% of all kidney transplantations in the United States. It is important ensure that the patient does not have active SLE disease at the time of transplantation. A 3-month period of dialysis is usually prudent in the event of spontaneous renal recovery.

Substantial evidence shows that patients with SLE fare worse than patients without SLE in terms of graft survival. Living-related allografts show better outcomes than cadaveric allografts. In patients with SLE, reasons for a more severe outcome after transplantation include recurrent lupus nephritis and concomitant antiphospholipid antibody syndrome resulting in allograft loss.[80]

It is frequently advisable to consult a nephrologist for renal biopsy or, if desired, for help in the management of renal disease.

The experience of pathologists in reading lupus nephritis biopsy specimens varies considerably. The most consistent readers of these specimens are usually found in larger academic centers that have substantial populations of patients with SLE.

American College of Rheumatology

Guidelines for managing lupus nephritis were published by the American College of Rheumatology in 2012.[81]  Key points of the guidelines are as follows:

• Patients with clinical evidence of active, previously untreated lupus nephritis should have a kidney biopsy to classify the disease according to International Society of Nephrology/Renal Pathology Society criteria

• All patients with lupus nephritis should receive background therapy with hydroxychloroquine, unless contraindicated; this recommendation was based on a prospective controlled trial showing lower flare rates in those who continued hydroxychloroquine, compared with those who switched to placebo[82]

• Glucocorticoids plus either cyclophosphamide intravenously (IV) or mycophenolate mofetil orally for induction in patients with class III and IV disease; patients with class I and II nephritis do not require immunosuppressive therapy

• Administer ACEIs or ARBs if proteinuria is 0.5 g/24 h or more

• Maintain blood pressure at or below 130/80 mm Hg

European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association

In 2019, the joint guidelines for the management of adult and pediatric lupus nephritis (LN) were updated by the European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA). The EULAR/ERA-EDTA revised recommendations include the following[64] :

• Goals of treatment include patient survival, long-term preservation of kidney function, prevention of disease flares, prevention of organ damage, management of comorbidities and improvement in disease-related quality of life.
• Kidney biopsy should be considered when there is evidence of kidney involvement, especially in the presence of persistent proteinuria ≥ 0.5 g/24 hours (or urine total protein to creatinine ratio ≥ 500 mg/g in morning first void urine), and/or an unexplained decrease in glomerular filtration rate (GFR)
• Initial treatment for class III–IV LN: Mycophenolate mofetil (MMF) or or low-dose IV cyclophosphamide plus glucocorticoids 
• Alternate option for class III–IV LN: Combination therapy of MMF with a calcineurin inhibitor (CNI), especially tacrolimus, particularly in patients with nephrotic-range proteinuria
• To reduce cumulative glucocorticoid dose: Intravenous pulses of methylprednisolone (total dose 500–2500 mg, depending on disease severity), followed by oral prednisone (0.3–0.5 mg/kg/day) for up to 4 weeks, tapered to ≤7.5 mg/day by 3 to 6 months
• Initial treatment for pure class V disease with nephrotic-range proteinuria: MMF in combination with methylprednisolone followed by oral prednisone 
• Alternate options for pure class V:  IV cyclophosphamide or a CNI, especially tacrolimus, as monotherapy or in combination with mMMF/mycophenolic acid (MPA)
• In all LN patients: Hydroxychloroquine (HCQ) should be coadministered at a dose not to exceed 5 mg/kg/day and adjusted for the GFR, in the absence of contraindications
• Patients who improve after initial treatment should receive MMF/MPA (especially if it was the initial treatment) or azathioprine (preferred in women who may become pregnant) in combination with low-dose prednisone when needed to control disease activity
• Gradual withdrawal of treatment (glucocorticoids first, then immunosuppressive drugs) can be attempted after at least 3 to 5 years therapy in patients with complete clinical response. HCQ should be continued long-term.
• Continuation, switching to or addition of CNIs, especially tacrolimus, can be considered in pure class V LN at the lowest effective dose and after considering nephrotoxicity risks
• Patients in whom initial therapy fails should be switched to one of the alternative initial therapies or to rituximab

Single Hub and Access point for pediatric Rheumatology in Europe

A European initiative, the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) project, has published guidelines on the diagnosis and treatment of childhood-onset LN.[83, 84]

Diagnostic recommendations from SHARE include the following[84] :

• Although pediatric patients with LN may present with renal dysfunction, hypertension, and macro- or microscopic hematuria and proteinuria, percutaneous kidney biopsy is required because symptoms alone do not reflect disease severity
• For patients with proteinuria and/or a low GFR, consult with a pediatric nephrologist to discuss the need for biopsy
• Consult with an experienced renal pathologist to evaluate kidney biopsies
• Exclude orthostatic proteinuria, which is the leading cause of proteinuria in teenagers, by collecting a first-morning urine sample; in girls, avoid collecting samples during menstruation

SHARE recommends complete renal response as the treatment goal in LN, with an early-morning urinary protein/creatinine ratio of less than 50 mg/mmol and normal kidney function. Patients should achieve a partial response within 6 to 12 months after starting treatment.[84] Treatment recommendations include the following:

• Immunosuppressive treatment should be guided by kidney biopsy results; when biopsy is not possible, patients with nephrotic syndrome, hypertension, and impaired kidney function should be treated as for class IV LN.
• In patients with proteinuria, consider adding an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

SHARE recommendations for management based on the International Society of Nephrology/Renal Pathology Society 2003 classification system include the following[84] :

• Class I: Treatment should be guided by symptoms
• Class II: Low-dose prednisone, followed by a disease-modifying antirheumatic drug in patients who have 3 months of persistent proteinuria or develop prednisone dependency.
• Class III/IV: Induction with MMF or intravenous cyclophosphamide plus steroids; maintenance treatment for at least 3 years with MMF, azathioprine, or both
• Class V: MMF with low-dose prednisone for induction; maintenance treatment with MMF

Kidney Disease: Improving Global Outcomes

Kidney Disease: Improving Global Outcomes (KDIGO) updated its guidelines on management of LN in 2021.[85] For diagnosis of LN nephritis, the guidelines recommend testing for kidney involvement at the initial presentation of systemic lupus erythematosus (SLE) and any suspicion of an SLE flare. The guidelines provide an algorithm for kidney function testing in SLE patients. Treatment recommendations include the following:

The total duration of initial immunosuppression plus combination maintenance immunosuppression for proliferative LN should not be < 36 months.

For class V LN, management based on proteinuria level

An algorithmic approach to patients whose response to therapy is deemed unsatisfactory

In patients whose LN relapses after a complete or partial remission has been achieved, the relapse should be treated with the same initial therapy used to achieve the original response, or an alternative recommended first-line therapy

Patients with LN and thrombotic microangiopathy (TMA) should be managed according to the underlying etiology of TMA, as determined by results of tests for ADAMTS12 activity and antibodies, and antiphospholipid antibodies. In adults, plasma exchange and glucocorticoid therapy should be started while awaiting test results.

Patients with active LN should be counseled to avoid pregnancy while the disease is active or when treatment with potentially teratogenic drugs is ongoing, and for ‡6 months after LN becomes inactive

To reduce the risk of pregnancy complications, hydroxychloroquine should be continued during pregnancy, and low-dose aspirin should be started before 16 weeks of gestation.

Only glucocorticoids, hydroxychloroquine, azathioprine, and CNIs are considered safe immunosuppressive treatments during pregnancy.

Treat pediatric patients with LN using immunosuppression regimens similar to those used in adults, but consider issues relevant to this population, such as dose adjustment, growth, fertility, and psychosocial

factors, when devising the therapy plan.

Patients with LN who develop kidney failure may be treated with hemodialysis, peritoneal dialysis, or kidney transplantation; however, kidney transplantation is preferred over long-term dialysis.

• Treat all patients with LN with HCQ or an equivalent antimalarial unless contraindicated.

• In all patients with LN, consider adjunctive therapies to manage LN and attenuate complications of LN and its treatment, including cardiovascular risk, proteinuria, infection risk, bone injury ultraviolet light exposure, premature ovarian failure, unplanned pregnancy and cancer

• In patients with active class III or IV LN, with or without a membranous component, treat initially with glucocorticoids plus either low-dose intravenous cyclophosphamide or a mycophenolic acid analogue (MPAA; ie, MMF or MPA).

• A regimen of reduced-dose glucocorticoids following a short course of methylprednisolone pulses may be considered during the initial treatment of active LN when both the kidney and extrarenal disease manifestations show satisfactory improvement.

• In patients with active class III-IV LN who may have difficulty adhering to an oral regimen, use intravenous cyclophosphamide as the initial therapy.

• An MPAA-based regimen is the preferred initial therapy of proliferative LN for patients at high risk of infertility; patients who have a moderate to high prior cyclophosphamide exposure; and patients of Asian, Hispanic, or African ancestry.

• Initial therapy with a triple immunosuppressive regimen that includes a CNI (tacrolimus or cyclosporine) with reduced-dose MPAA and glucocorticoids is reserved for patients who cannot tolerate standard-dose MPAA or are unfit for or will not use cyclophosphamide-based regimens.

• In patients with baseline eGFR of at least 45 mL/min/1.73 m2, voclosporin can be added to MPAA and glucocorticoids as initial therapy for 1 year.

• There is an emerging role for B-lymphocyte targeting biologics (rituximab, ocrelizumab) in the treatment of LN. Belimumab can be added to standard therapy in the treatment of active LN. Rituximab may be considered for patients with persistent disease activity or repeated flares.

• Other therapies, such as azathioprine or leflunomide combined with glucocorticoids, may be considered in lieu of the recommended initial drugs for proliferative LN in situations of patient intolerance, lack of availability, and/or excessive cost of standard drugs, but these alternatives may be associated with inferior efficacy, including increased rate of disease flares and/or increased incidence of drug toxicities.

• After completion of initial therapy for class III-IV LN, patients should be placed on MPAA for maintenance. After tapering of prednisone to < 5-7.5 mg/d, the first choice is an MPAA.

• Glucocorticoids should be tapered to the lowest possible dose during maintenance, except when glucocorticoids are required for extrarenal lupus manifestations; discontinuation of glucocorticoids can be considered after patients have maintained a complete clinical renal response for ≥12 months.

• The dose of MMF in the early maintenance phase is approximately 750–1000 mg twice daily, and for MPA, approximately 540–720 mg twice daily.

• Azathioprine, 1.5-2.00 mg/kg/d, is an alternative to MPAA after completion of initial therapy in patients who do not tolerate MPAA, who do not have access to MPAA, or who are considering pregnancy.

• If MPAA and azathioprine cannot be used for maintenance, consider CNIs (tacrolimus, cyclosporine) or mizoribine.

• The total duration of initial immunosuppression plus combination maintenance immunosuppression for proliferative LN should not be < 36 months.

• For class V LN, the guidelines provide algorithms for management, based on proteinuria level, and on treatment of patients whose response to therapy is deemed unsatisfactory.

• In patients whose LN relapses after a complete or partial remission has been achieved, the relapse should be treated with the same initial therapy used to achieve the original response, or an alternative recommended first-line therapy.

• Patients with LN and thrombotic microangiopathy (TMA) should be managed according to the underlying etiology of TMA, as determined by results of tests for ADAMTS12 activity and antibodies, and antiphospholipid antibodies. In adults, plasma exchange and glucocorticoid therapy should be started while awaiting test results.

• Patients with active LN should be counseled to avoid pregnancy while the disease is active or when treatment with potentially teratogenic drugs is ongoing, and for at least 6 months after LN becomes inactive.

• To reduce the risk of pregnancy complications, HCQ should be continued during pregnancy, and low-dose aspirin should be started before 16 weeks of gestation.

• Only glucocorticoids, HCQ, azathioprine, and CNIs are considered safe immunosuppressive treatments during pregnancy.

• Treat pediatric patients with LN using immunosuppression regimens similar to those used in adults, but consider issues relevant to this population, such as dose adjustment, growth, fertility, and psychosocial factors, when devising the therapy plan.

• Patients with LN who develop kidney failure may be treated with hemodialysis, peritoneal dialysis, or kidney transplantation; however, kidney transplantation is preferred over long-term dialysis.

Corticosteroids are used in all patients with clinically significant renal disease. Immunosuppressive agents, particularly cyclophosphamide, azathioprine, and mycophenolate mofetil, are used in patients with aggressive renal lesions because they improve the renal outcome. They may also be used in patients with inadequate response or excessive toxicity to corticosteroids. Cyclosporine and tacrolimus have been used in some cases.

Class Summary

Corticosteroids are very useful in controlling acute inflammatory manifestations of systemic lupus erythematosus (SLE). Alone, they may be adequate in treating milder forms of lupus nephritis with a lower risk of progressive renal dysfunction, such as minimal mesangial lupus nephritis, mesangial proliferative lupus nephritis, early focal lupus nephritis, or membranous lupus nephritis. Oral corticosteroids can be used in most patients. If adequate absorption is a concern (eg, bowel edema in a patient with nephrosis), intravenous (IV) methylprednisolone can be used.

Prednisone

Prednisone is commonly used to treat inflammatory manifestations of SLE. Treatment of clinically significant lupus nephritis should include moderate-to-high doses initially.

Methylprednisolone (Medrol, Solu-Medrol, A-Methapred)

Methylprednisolone is used in much the same manner as prednisone. It is more potent: 4 mg of methylprednisolone is equivalent to 5 mg of prednisone. Intravenous dosing is used in the inpatient setting.

Class Summary

In particular, cyclophosphamide, mycophenolate, and azathioprine are used in patients with aggressive renal lesions (eg, focal or diffuse lupus nephritis) because they improve renal outcome. These agents can also be used in patients with inadequate response or excessive toxicity to corticosteroids. Mycophenolate mofetil has been shown to be effective for treatment of lupus nephritis. Mycophenolate mofetil was found to be superior to azathioprine in maintaining control and preventing relapses of lupus nephritis in patients who have responded to induction therapy.[62]

Cyclophosphamide

Cyclophosphamide is indicated for treatment of most patients with focal lupus nephritis or diffuse lupus nephritis. Although it has significant toxicity, it has been shown to prevent the progression of nephritis and improve renal outcome.

Azathioprine (Imuran, Azasan)

Azathioprine is useful in moderate-to-severe lupus nephritis. It improves renal outcome, but it does not appear to be as effective as cyclophosphamide, although it is less toxic.

Mycophenolate mofetil (CellCept) or mycophenolic acid (Myfortic)

Mycophenolate mofetil is an option for induction therapy with class III/IV lupus nephritis. It has generally been well tolerated and, in several studies, has been as effective as (and possibly more effective than) more traditional therapies, including cyclophosphamide and azathioprine, with less toxicity. The American College of Rheumatology guidelines recommend mycophenolate mofetil as the preferred agent for African Americans and Hispanics.

Hydroxychloroquine (Plaquenil)

The exact anti-inflammatory mechanism of action of hydroxychloroquine is not well understood. Its effect is thought be related to increasing the pH within intracellular vacuoles, which alters protein degradation by acidic hydrolases in the lysosomes and assembly of macromolecules in the endosomes and the Golgi apparatus. Acidic pH is required for protein antigen processing for presentation on antigen-presenting cells with MCH class II receptors. The ultimate effect of hydroxychloroquine is to reduce antigen presentation by antigen-presenting cells to CD4- positive T lymphocytes, resulting in downregulation of the immune response. The American College of Rheumatology guidelines recommend that all patients with SLE and nephritis be treated with a background of hydroxychloroquine, unless contraindicated.

Belimumab (Benlysta)

Monoclonal antibody blocks the binding of BLyS (a B-cell survival factor) to B-cells. It inhibits the survival of B-cells and reduces B-cell differentiation into immunoglobulin-producing plasma cells. It is indicated for the treatment of active lupus nephritis in adults who are receiving standard therapy.

Rituximab (Rituxan, Riabni, Rituximab-abbs)

Monoclonal chimeric antibody directed against CD20 and induces a long-lasting B-cell depletion. Rituximab has been used as off-label treatment for lupus nephritis. It is recommended by EULAR/ERA-EDTA as an alternative option for nonresponsive class III to V lupus nephritis.

Class Summary

Through the inhibition of calcineurin, these therapies reduce cytokine activation, block interleukin IL-2 expression and T-cell mediated immune responses.

Cyclosporine (Gengraf, Neoral, Sandimmune)

Cyclosporine inhibits production and release of interleukin II and interleukin II-induced activation of resting T-lymphocytes. Use is not approved by the FDA but recommended by EULAR/ERA-EDTA as an alternative option for pure class V lupus nephritis.

Tacrolimus (Astagraf XL, Envarsus XR, Hecoria)

Tacrolimus is an immunosuppressive agent that inhibits of calcineurin-induced dephosphorylation of synaptopodin, a critical protein that regulates actin filaments of the podocyte cytoskeleton. Use is not approved by the FDA but recommended by EULAR/ERA-EDTA as an alternative option for pure class V lupus nephritis. 

Voclosporin (Lupkynis)

Novel high potency calcineurin-inhibitor reduces T-cell activation and stabilizes podocytes, which protect against proteinuria. First oral therapy approved in combination with immunosuppressive therapy for lupus nephritis